18-oxygenated steroids and process for their synthesis



United States Patent 0 2,994,694 IS-OXYGENATED STEROIDS AND PROCESS FOR THEIR SYNTHESIS Albert Wettstein, Georg Anner, and Karl Heusler, Basel, Hellmut Ueberwasser, Riehen and Peter Wieland, Julius Schmirllin, and Jean-Rene Billeter, Basel, Switzerland, assignors to Ciba Pharmaceutical Products, Inc., Summit, NJ.

No Drawing. Filed Nov. 28, 1958, Ser. No. 776,690 Claims priority, application Switzerland July 30, 1954 34 Claims. (Cl. 260239.57)

This is a continuation in part of our copending application Serial No. 521,398, filed July 11, 1955.

Among the l8oxygenated steroids, the hormone aldosterone isolated from adrenal glands, is of extreme importance, more especially because of its specific efiect on the mineral metabolism. Since, however, on one hand, the quantities in which it occurs in animal organs are too small for producing the hormone economically, and since, on the other hand, it has hitherto not been possible to prepare aldosterone by partial synethesis from other naturally occurring steroids, its manufacture by total synthesis is of considerable industrial importance.

The present invention provides a new process for synthesizing aldosterone and its derivatives in a simple man- Part A: O/ X v 2,994,694 Patented Aug. 1, 1 961 ner from a A -3:l6-dioxo-l1p:18a-oxido-l8a-methyl- 1'8-homoandrostadiene of the formula or from a corresponding 3-ketal which may contain a 15 further double bond in the 14:15-position.

The new process can be subdivided into four main parts:

(A) Degradation of the cyclic enol ether grouping at ring C to the l8:l1cyclo-semiacetal structure typical of aldosterone;

20 (B) Condensation with an oxalic acid ester in the l7-po- 25 (-1)) Conversion of the side chain into the ketol side chain of aldosterone.

One variant of the synthesis is represented by the following formula scheme:

' CHO o o 8 i-n aee 0504 0 m lNaOGH:

The present patent applicationis concerned with Part A of the process described above, that is to say with the degradation of the cyclic enol ether to 18:11-cyclo-semiacetal.

According to the present process the 18:18a-double bond in a A -3:16-dioxo-1l/3:l8a-oxido-18a-methyl-l8- homo-androstadiene of the formula which may contain a further double bond in the 14:15- position, or in a corresponding 3-ketal, is subjected to oxidative cleavage and, in the resulting llB-acetoxy-lS- oxo-compound, the llfi-acetoxy group is hydrolyzed in an alkaline medium; if a 14:15-double bond is present, it or the 16-oxo group is temporarily protected; if desired, the semi-acetal group is functionally converted, and, if desired, the 14: l5-double bond is hydrogenated at any stage of the process.

The cleavage of the 18:18a-enol double bond is performed, for example in the manner generally known for the oxidative cleavage of double bonds. The ozonides, obtained by the action of ozone, are split under reducing conditions, for example with zinc and acetic acid, zinc and ethanol, noble metal catalysts (e.g. palladium, platinum) on a support (eag. charcoal, barium sulfate or other standard support) with hydrogen or any other standard technique for such reductive process. The cleavage of the enol double bond can be performed even by oxidation with compounds of hexavalent chromium, for example with chromic acid in pyridine. It is also possible to hydroxylate the enol double bond in a manner known per se, for example by reaction with a molecular proportion of osmium tetroxide, potassium permanganate, etc., the resulting glycol being split up with per-iodic acid, lead tetra-acetate, sodium bismuthate, etc. Particularly advantageous results have been achieved with a new, ex-- tremely mild hydroxylation method, according to which the oxidation is performed with an alkali metal perhalate, such as the perchlorate and particularly the per-iodate, for example with'sodiurnper-iodate in the presence of a catalytic amount of osmium tetroxide with the addition of an alkali metal salt of a carboxylic acid (particularly a lower fatty acid), such as potassium acetate, in an aqueous medium. This procedure :gives an almost quantitative yield of the glycol which can be split with the aid of the per-iodic acid or other equivalent reagent. When pyridine instead of potassium acetate is used as buffer, the llfi-acetoxy-lS-oxo compound is formed directly, instead of the glycol.

By virtue of the presence of the l8-oxo group the 11,6- acetoxy group can be hydrolyzed even under relatively mild conditions. For example, there may be used an alkali metal carbonate, such as potassium carbonate in an inert solvent, such as aqueous methanol or dioxane. Transesterification may also be eifected to yield the same result by means of a solution of an alkali metal in an absolute lower alkanol, e.g. sodium methoxide, potassium ethoxide. As a rule, a temperature about 20 C. will suflice to complete the reaction within a few hours. The llfi-hydroxy-lS-oxo compounds produced by the hydrolysis are-at least in solutionalmost entirely present in the formof cyclo-semiacetals.

If desired, the free hydroxyl group of the cyc1o-semiacetal can be esterified, etherified or oxidized to an oxo group. The esterification is conducted in a manner known per se with a reactive derivative of a carboxylic acid, such as an acid anhydride or halide in the presence of an acidacceptor such as pyridine. Suitable esterifying agents are reactive derivatives of fatty acids; particularly lower fatty acids as well as aromatic acids, particularly monocyclic' carbocyclic aromatic acids, for example, the anhydrides or acid halides of acetic acid, propionic acid or butyric acid, or benzoyl chloride or trimethylacetic acid chloride. Alternatively, the 18-esters can be prepared by transesteri fic-ation, for example by heating an 18-ester of a lowboiling acid with a salt of a high-boiling acid, such as ain the formic acid esters, such as the methyl, ethyl (i.e. lower alkyl) or benzyl ester of orthoformic acid, and more particularly dihydropyran. Both the esters and the ethers are easy to split off again, for example by a short heat treatment in an aqueous carboxylic acid, such as aqueous acetic acid or other lower fatty acids etc. The esters can.

- also be split by mild alkaline hydrolysis with alkali metal bicarbonate, carbonates, alkoxides, alkali and alkaline Examples of these standard earth metal hydroxides. reagents are sodium bicarbonate, potassium carbonate, sodium ethoxide, sodium propoxide, lithium isopropoxide, lithium hydroxide, sodium hydroxide, barium hydroxide,

etc.

The cyclo-serniacetal groupis easy to oxidize to the lactone group. This can be performed with compounds of hexavalent chromium, such aschromic acid in pyri-. dine, chromic acid in glacial acetic acid, sodium bichromate, or with other oxidants such as manganese dioxide.

When the cleavage of the cyclic enol. ether is performed on a A -l6-keto compound, the 11 B-acetoxy group can be hydrolyzed only after the sensitive vinylogousfi-ketoaldehyde grouping of the A -11fi-acetoxy-16:18-dioxo compound formed has been protected. Thiscan be achieved, for example, by ketalizing one of the two 0x0 groups with a 1:3- or a lz2-glycol particularly a lower alkylene glycol, such as ethylene glycol or propylene :glycol, or by conversion into a (l) thioketal or (2) semithioketal, for example with (l) a lower alkylene mer-.

captan (e.g. ethylene mercaptan) or (2) a mercapto lower alkanol (erg. mercaptoethanol) in the presence of a ketalization catalyst, for example with pyridine hydrochloride. With ethylene glycol, ior example, an 18-ketal is formed, and with ethylene mercaptan a 16-thioketal. The thioketals are particularly suitable for temporary protection because they can be split again to yield the ketone, for example with the aid of a mercury or cadmium salt, in a selective manner, that is to say without affecting any other ketal group, for example in the 3-position.

Alternatively, the A -16-oxo grouping can be so converted before the oxidative cleavage of the enol double bond that the sensitive A -18-oxo-16-ketone does not occmat all as an intermediate in the subsequent reactions. Thus, for example, the l6-keto group in the starting material can be reduced to the carbinol with a complex metal hydride, such as lithium-aluminum hydride, lithium-boron hydride or sodium-boron hydride, etc. The oxidative cleavage of the enol ether double bond in the manner described above yields a A -1lfi-acetoxy-l8-oxo-l6 hydroxy-compound which can then be hydrolyzed to the cyclo-semiacetal. The 16-hydroxy group is then oxidized to the 16-oxo group, for example with the aid of manganese dioxide.

An especially advantageous order of sucession of the reactions leading to the cyclo-semiacetal derivatives;

of reactions the 3-keta1 of A 1 -3:16-dioxo-1lfizl8aoxido-18a-methyl-18 homo-androstatriene, used as starting material, is converted with hydrogen peroxide in an alkaline solution into the corresponding 14:15-epoxide. It is surprising that in this reaction the enol double bond is not aifected. The 18:18a-eno1 double bond in the resulting epoxide is then subjected to oxidative cleavage as described above, and the llfi-acetoxy group is hydrolyzed. Before or after the esterification or etherification of the cyclo-semiacetal group the 14:15-epoxide is then opened up to the 14-hydroxy compound by catalytic hydrogenation, preferably in the presence of a noble metal (e.g. palladium) catalyst on a support such as charcoal, calcium carbonate, barium sulfate or zinc carbonate. The 14:15-double bond is then reintroduced by elimination of water from the l4-hydroxy-l6-ketone, advantageously under alkaline conditions. Suitable water-eliminating agents are also salts such as piperidine benzoate or acetate or triethylamine benzoate. The elimination of water is particularly easy by heating with alumina in an inert solvent such as benzene, toluene or the like. The retention or temporary. protection and subsequent reintroduction of the 14:15-double bond is of considerable importance because it has been observed that the steric course of the catalytic hydrogenation of this double bond depends surprisingly on the substitution at the carbon atom in the 18-position. With the cyclic enol ethers used as starting materials for the present process, as well as with the 11fi-acetoxy-l8-oxo compounds obtained by oxidative cleavage of the enol double bond, a preponderance of the unnatur l4fl-compounds is obtained by the catalytic hydrogenation. On the other hand, the A 16-oxo compounds containing 18: 1l-cyclo-semi-acetal groups or l8zll-lactone groups yield almost exclusively the natural I la-compounds having trans-linked rings C and D. Thus, to ensure a high yield of 140t-0OIHPOl1I1dS, it is of advantage to introduce the 18:1Lcyclo-semiacetal grouping before the 14: l-double bond is hydrogenated.

If desired, A -3zl6-dioxo compounds can be converted into 3-monoketals by ketalization with methylethyl dioxolane in the presence of a catalytic quantity of paratoluenesulfonic acid, as has been previously disclosed in Indian Patent No. 52,534 corresponding to US patent application Serial No. 521,398, filed July 11, 1955.

The 14:15-saturated llz'l8-dioxygenated A -3zl6-dioxoandrostenes, more especially their 3-ketals, can be converted into the corresponding 18:1l-lactones in the manner described hereinbefore as well as in the examples. A l7-carbalkoxy group can be introduced in said lactones according to the process of Indian application No. 61,333 corresponding to US. patent application Serial No. 747,346, filed July 9, 1958, by condensation with a carbonic acid ester. Enolacetylation and hydrogenolytic elimination'of the enolacetate group yields the 16-unsubstituted acetic ester which is converted into aldosterone as disclosed in Indian Patent No. 51,359 corresponding to US. patent application Serial No. 480,061, filed January 5, 1955, and now US. Patent No. 2,904,545.

' The present invention also provides 11:18-dioxygenated 16-oxo-androstanes, more especially llfi-acyloxy-l6zl8- dioxo-androstanes, A -3zloz-l8-trioxo 11p acetoxyandrostadiene, A -3:16:=l8-trioxo 115 acetoxy-l4z15- oxido-llp-androstene the free, esterified and etherified 18:11-cyclo-semiacetals of llp-hydroxy 16: 18 dioxoandrostanes, e.g. A -3:16:l8-trioxo-1lB-hydroxy-an'drostene, of A -3 :16: l8-trioxo-l1,B-hydroxyandrostadiene, of A -3:16:18-trioxo-11p-hydroxy 14:15 oxido androstene, of A -3zl6zl8-trioxo-llfiz14-dihydroxy-androstene; the 18:11-lactone of M6 :16-dioxo-1lfi-hydroxyandrostene-18-acid; the l8zll-lactone of A -3:l6-dioxo-1l,3- hydroxy-androstadiene-l8=acid; as well as the 3-ethylene ketals of the afore-mentioned compounds.

These compounds are valuable intermediates for the manufacture of aldosterone and of its derivatives.

jIhe'products of the present process are racemates or The present invention also covers variants of the process in which only some of the steps are performed, if desired in a different order of succession, or in which the starting material used is an intermediate obtained at any stage of the process and the remaining step or steps are carried out.

The following examples illustrate the invention.

Example 1 A solution of 290 mg. of osmium tetroxide in 10 cc. of absolute ether is stirred into a solution of 340 mg. of dzl A 3:16 dioxo -11 3:'18a oxido 18a methyl- 18-homo-14-iso-androst-adiene in 20 cc. of absolute tetrahydrofuran and 0.22 cc. of pyridine. After 1 hour the stirrer is switched off, and the reaction solution is kept overnight at room temperature; the adduct crystallizes out but can be dissolved again by adding 100 cc. of methanol. A solution of 4 grams of ammonium sulfite in 100 cc. of water is then stirred in and after 1 hours Celite is added to make the precipitate formed easier to filter. After filtration through a layer of Celite and washing its filter residue with 500 cc. of methanol, the filtrate is concentrated in vacuo at 50-60 C. to about 50 cc. and extracted 4 times with 50 cc. of a mixture of 7 parts of chloroform and 3 parts of alcohol. The chloroform/alcohol extracts are separately shaken with 60 cc. of semi-saturated common salt solution. The residue (320 mg.) of the dried and evaporated organic solution is dissolved in 7.5 cc. of methanol and 1.25 cc. of pyridine, and 1.5 cc. of a 0.912 N-solution of periodic acid are added. The mixture is kept for 1 hour at room temperature, 50 cc. of semi-saturated common salt solution are added, and the whole is extracted four times with 50 cc. of chloroform. The chloroformic solutions are washed with 50 cc. of semi-saturated common salt solution, dried, and evaporated in vacuo, and the residue is chromatographed over 9 grams of alumina (activity 11). The benzene, ether and ether/ethyl acetate (9:1) eluates contain d:l-A -3:16:18-trioxo-11fi-acetoxy-14-isoandrostene (146.5 mg.) which, after dissolution in and crystallization from acetone/ether, melts at 16-1-165.5 C. The infrared spectrum (solvent: methylene chloride) displays the following bands in the carbonyl area: 3.67;/. (aldehyde); 5.72 4, broad (aldehyde-l-ester-l-S-ring-CO) and 5.96n+6.15,u (mp-unsaturated carbonyl).

A solution of 25 mg. of the above llfi-acetate and 100 mg. of potassium carbonate in 6 cc. of alcohol and 3 cc. of water is refluxed for 1 hour in -a current of nitrogen, the reaction mixture is poured into semi-saturated common salt solution and extracted once with benzene and three times with chloroform. The organic solutions are washed with saturated common salt solution, dried, and evaporated; dissolution of the residue in acetone+ether and recrystallization yields d:l-A -3:l6:1'8-triox0-l1}3-hydroxy-14-iso-androstene cyclo-semiacetal melting at 221- 226 C. In the infrared spectrum (solvent: methylene chloride) the aldehyde band at 3.67 1 can no longer be seen. Characteristic bands appear at 2.7-8n (hydroxyl), 5.72;. (S-ring-ketone band) and at 5.97,u.+6.l7n (the A 3-ketone bands).

The hydrolysis can alternatively be performed by keeping a solution of 41.8 mg. of the llfi-acetate and 54 mg. of potassium carbonate in 6.5 cc. of methanol and 1.75 cc. of water for 22 hours in an evacuated arnpoule at room temperature.

Example 2 7.0 grams of d:l-A -3-ethylenedioxy-l1p:18a-oxidol6-oxo-18a-methyl-l8-homo-androstatriene, dissolved in 10 cc. of dry pyridine and cc. of chloroform, are

. 9 treated for 28.5 minutes at 15 to -18 C. with turbination with a current of oxygen containing ozone, capable of supplying 24.5 mg. of ozone per minute to the reaction mixture. When the reacted gases are passed through a first specimen of a mixture of 0.5 cc. of 0.02 N-thiosulfate solution, 1 cc. of potassium iodide solution of 10% strength, 0.5 cc. of starch solution and 0.5 cc. of 2 N-acetic acid, it turns brown-violet after 28 minutes. The change in color of the subsequent second test occurs after 30 seconds. The oxygen is then displaced by nitrogen, and the ozonides formed-after addition of a mixture, pre-cooled to --l C., of 10 cc. of Water, 20 cc. of pyridine and 10 cc. of glacial acetic acidare reduced with 15 grams of zinc powder in the form of a paste moistened with water and activated with dilute acetic acid, during which the temperature rises temporarily to -50 C. The reaction mixture is once again cooled to 7 C., and the unreacted zinc is filtered off and rinsed with benzene. The filtrate is washed repeatedly with water and then with sodium bicarbonate solution of 10% strength, four times with 100 cc. of ice-cold 1.5 N-phosphoric acid on each occasion, once again with water, and finally with bicarbonate solution. The whole is dried, and the solvents are removed in vacuo. Addition of 2 cc. of methylene chloride and 10 cc. of ether to the crude product causes the crystallization of 3.3 of dzl-A -3-ethylenedioxy-1le-acetoxy- 16: 18-dioxo-androstadiene which, after dissolution in and crystallization from benzene, melts at 188-189 C. Infrared spectrum in methylene chloride; no hydroxyl band; at 3.7;; (aldehyde); broad band at 5.75;;-5.82;; with infiexion at 5.9;; (ester, aldehyde, l6-carbonyl); 6.22;; (A 8.16;; (acetate); 9.1;; (ketal). Ultraviolet spectrum Example 3 500 mg. of dzlA -3-ethylenedioxy-11fi:l8a-oxido-16- oxo-lSa-methyl-l8-homo-l4-iso-androstadiene are stirred with ice-cooling into 500 mg. of chromium trioxide in 6 cc. of absolute pyridine. The mixture is stirred for 20 hours at room temperature, semi'saturated common salt solution and benzene are added, and the whole is filtered through Celit'e. The filter residue is washed with benzene and then with water, and the aqueous phase of the filtrate is then extracted twice with benzene. The benzolic solutions are twice washed with semi-saturated common salt solution, dried and evaporated in vacuo; the residue is chromatographed over 15 grams of alumina (activity II). The first benzene fractions contain starting material. The subsequent benzene eluates contain dzlA 3 ethylenedioxy 16:18 dioxo 11;3 acetoxy- 14-iso-androstene which, after dissolution in and crystallization from ether, melts at 171-172 C. The infrared spectrum (solvent: methylene chloride) displays the following characteristic bands: 3.68;; (aldehyde); 5.75;; intensive (aldehyde}5-ring-CO+ester); 8.14;; (acetate) and 9.15;; (ketal).

Example 4 1.0 gram of d:lA5= ,-3-ethylenedioxy-115:18a-oxido-16- oxo-l8a-methyl-l8-homo-14-iso-androstadiene, dissolved in 5 cc. of pyridine and 50 cc. of chloroform, is treated as described in Example 2 for 33 minutes with an ozonecontaining current of oxygen capable of supplying 5.28 mg. of ozone per minute, and worked up as described in Example 2. The resulting d:l-A -3-ethylenedioxy115- acetoxy-16:18-dioxo-14-iso-androstene is completely identical with the compound described in Example 3.

The same compound canralternatively also be prepared from the d:l-A 14-3-ethylenedioxy-11fi-acetoxy-l6:18-dioxo-androstadiene described in Example 2 in the following manner:

400 mg. of this compound are hydrogenated in 60 cc. of absolute ethanol under atmospheric pressure and at room temperature with the use of 200 mg. of a palladiumcarbon catalyst containing of palladium. When approximately one molecular equivalent of hydrogen has been taken up (which takes about 10 hours), the hydrogenation comes to a standstill. The catalyst is filtered 0E, and the filtrate is evaporated in a water-jet vacuum. The crude product still displays an extinction of 4400 (about 30% of A -16-ketone) at 233 m/;;; it is chromatographed over 12 grams of alumina (activity '11). From the fractions elutriated with benzene and with 9:1 benzene+ethyl acetate, there is obtained by crystallization from methanol a total of 195 mg. of d:l-A -3-ethylenedioxy-l 1 fi-acetoxy-lo 1 8-dioxo-14-isoandrostene melting at 171-172 C. The fractions elutriated with 2:1 mixtures of benzene and ethyl acetate are evaporated and the residue is crystallized from methylene chloride/ether to yield 40 mg. of dzl-A -3-ethylenedioxy-l1;8-acetoxy-16- oxo-lS-hydroxy-14iso-androstene melting at 226 C.

192 mg. of the above d:l-A -3-ethylenedioxy-l lfl-acetoxy-16:18-dioxo l4-iso-androstene are dissolved in 50 cc. of alcohol, a solution of 800 mg. of potassium carbonate in 25 cc. of water is added and the whole is refluxed for 1.5 hours under nitrogen at a bath temperature of C. The mixture is then cooled, the alcohol removed in a water-jet vacuum, and the aqueous solution is repeatedly extracted with 1:1 mixtures of benzene and ether. The organic extracts are washed with Water, dried and evaporated, to yield 173 mg. of a crystalline residue. After recrystallization from acetone-I-ether and methylene chloride-l-ether d 1-A -3-ethylenedioxy-1 1 B-hydroxy- 16 18-dioxo-14-iso-androstene cyclo-semiacetal which melts at 20821l C. is obtained. Infrared spectrum in methylene chloride: bands at 2.79;; and 2.95;; (free and combined hydroxyl); 5.74;; (16-CO); no further bands between 5.6;; and 6.5;;; 9.16;; (ketal).

80 mg. of the above semiacetal are kept for 24 hours at room temperature in 1.0 cc. of absolute pyridine and 0.5 cc. of acetanhydride. The mixture is then poured into 20 cc. of ice water and the white crystalline precipitate is suctioned off after 30 minutes. The crude product (87 mg.) is crystallized from acetone-l-ether. The pure semiacetal-acetate melts at 183185 C. Infrared spectrum in methylene chloride: no hydroxyl band; bands at 5.74;; (strong, ester+l6-CO); 8.15;; (ace' tate); 9.13;; (ketal).

mg. of the above cyclo-serniacetal of d:lA -3- ethylenedioxy 11B hydroxy 16:18 dioxo 14 isoandrostene are mixed with a solution of 300 mg. of chromium trioxide in 3 cc. of absolute pyridine with ice cooling and the mixture is stirred for 4 hours at room temperature, then poured into dilute common salt solution and extracted with benzene. The mixture is then filtered through Celite, and the filter residue is thoroughly washed with benzene. The benzolic layer of the filtrate is separated and Washed with dilute common salt solution. Each aqueous solution is once more extracted with benzene; the benzolic solutions are combined, dried and evaporated to dryness under diminished pressure. The residue is crystallized from acetone-I-ether and yields 120 mg. of the 18:11-lactone of dzl-A -3-ethylenedioxy- 1lfi-hydroxy-16-oxo-14-iso-androstene-18-acid melting at 196-197 C. Infrared spectrum in methylene chloride: bands at 5.62;; ('ylactone); 5.71;; (l6-CO) and 9.11;; (ketal).

Example 5 A solution of 10 grams of sodium-boron hydride in 200 cc. 70% methanol is mixed with stirring and cooling with ice water in a current of nitrogen with a solution of 10 grams of dzl-A -3-ethylenedioxy-11B:18a-oxido- 16-oxo-18a-methyl-18-homo-androstatriene in cc. of.

vacuo in a current of nitrogen at a bath temperature of 40-50 C., extracted three times with benzene, and the benzolic solutions are washed three times with water, dried and: evaporated in vacuo at 50 C. Finally, the mixture is dried for /2 hour at 50 C. in a high vacuum, then dissolved in 15 cc. of dry pyridine and 70 cc. of chloroform and for 63 minutes, at -15, an ozonized current of oxygen, capable of yielding 23 mg. of ozone per minute, is caused to react with turbination. The change in color of a test liquid, through which the reacted gases pass, containing 0.5 cc. of 0.02 N-thiosulfate solution, takes place after 54 minutes and 35 seconds. A corresponding third test solution changes color after 1 minute and 20 seconds. Working up is then performed in the-manner described in Example 2.

For hydrolysis the crude ozonization product is dissolved in.l liter of alcohol, mixed with 500 cc. of a potassium carbonate solution of 4% strength, and refluxed for 2 hours in a current of nitrogen. 15 cc. of glacial acetic acid are added, the mixture is extensively evaporated in vacuo in a current of nitrogen at a bath temperature of 55, 2 N-sodium carbonate solution is added, and the whole is extracted four times with 250 cc. of chloroform. The chloroform solutions are then washed with saturated common salt solution, dried and evaporated in vacuo in a current of nitrogen. Addition of a mixture of benzene, ethyl acetate and ether yields 2.96 grams of the 18:11-cyclo-semiacetal of d:l-A -3- ethylenedioxy-1 1,8: 16-dihydroxy- 1 s-oxo-androstadiene in the form of a pale-brown powder. The mother liquor is evaporated and the residue chromatographed over 60 grams of alumina (activity II), and with ethyl acetate and chloroform another 340 mg. of this compound are obtained.

The combined crystallizates (3.3 grams) are treated with 300 cc. of chloroform and oxidized for 5 hours by being stirred at room temperature with 25 grams of activated manganese dioxide. The mixture is filtered through Celite, the filter residue is washed with chloroform and the filtrate is evaporated in vacuo in a current of nitrogen, and the residue is repeatedly dissolved in and crystallized from acetone. The resulting 18:11-lactone of d:l-A 3 ethylenedioxy 11B hydroxy 16 oxo androstadiene-18-acid melts at 244-246.5 C. and its ultraviolet spectrum contains: (1) maximum at 221 m i (e=10,050), minimumat 228 mu (s=8650); (2) maximum at 241 my. (e=11,800). In the carbonyl area the infrared spectrum (solvent-methylene chloride) displays the following characteristic bands: 5.6a ('y-lactone) and 5.81;t+6.16,u (A -16 ketone). The residue'of the evaporated mother liquor of the lactone described above is dissolved in acetone and filtered through 3 grams of iron-free Norite, and the eluate is evaporated in vacuo. Crystallization from acetone-l-ether yields 760 mg. of a mixture melting at l77-203 C. which is acetylated overnight with cc. of pyridine and 5 cc. of acetanhydride. The reaction mixture is evaporated in a high vacuum at a bath temperature of 50 C., the residue is dissolved in 5 cc. of benzene and chromatographed over 50 grams of silica gel. A 4:1 mixture of benzene and ethyl acetate at first elutriates a small amount of a compound melting at 222- 227 C. after recrystallization from benzene-l-ether which displays the following infrared spectrum (solvent: methylene chloride): 5.63,:1. -('y-lactone); 5.77,u+8.12/L (acetate),and 9.10, (ketal). The product is probably one of the two 16-isorneric18:11-lactones of the dzl-A -3- ethylenedioxy 116 hydroxy 16 acetoxy androstadiene-l8-acids.

j According to their infrared spectra the subsequent eluates obtained with 4:1 mixtures of benzene and ethyl acetate consist primarily of the cyclic semiacetal-acetate of (121,- A5114 3 ethylenedioxy 11,8 hydroxy 16:18-

dioxo-androstadiene. Towards the end further quantities of the 16-keto-lactone described above areelutriated.

"A solution of 239mg. of the A -16-keto-lactone described above in 150 cc. of absolute ethanol is stirred with 300mg. of a 10% palladium carbon catalyst under atmosphericpressure and at room temperature in a current of hydrogen. In the course of /2 hour one molecular equivalent of hydrogen is taken up. The reaction mixture is then suction filtered, the filter residue washed with methylene chloride, and. the filtrate evaporated to dryness in a water-jet vacuum. Recrystallization of the resulting residue (219 mg.) from methylene chloride-l-ether yields 200 mg. of the 18:11-lactone of dzl A -3 ethylenedioxy 11/3 hydroxy 16 oxoandrostene 18 acid melting at 263268 C. (I.V.). Infrared spectrum in methylene chloride: bands at 5.65m ('y-lactone); 5.71/,u (16-C0);9.14/,u. (ketal). Further processing is performed as described in US. Patent Application Serial No. 747,346, filed July 9, 1958.

Example 6 A solution of 150 mg. of osmium tetroxide in 8 cc. of ether is stirred into a solution of 200.4 mg. of d:1-A -3- ethylenedioxy 18a oxido 16 oxo 18a methyl- 18-homo-androstadiene in 10 cc. of absolute tetrahydrofuran and 0115 cc. of pyridine, whereupon a precipitate is formed after 40 minutes. The whole is kept for 20 hours at room temperature, diluted with 60 cc. of methanol, a solution of 2 grams of ammonium sulfite in 60 cc. of Water is stirred in. The mixture is stirred for 1 /2 hours, filtered through Celite, and the filter residue is washed with cc. of methanol. The filtrate is extensively evaporated at a bath temperature of 40 to 50 C. in a water-jet vacuum, diluted with saturated common salt solution and extracted once with 30 cc. of chloroform and three times with a 7:3 mixture of chloroform and alcohol. iIhe organic solutions are then washed separately once with 30 cc. of semi-saturated common salt solution, combined, dried and evaporated in vacuo. The crystalline residue is dissolved in 4.8 cc. of methanol and 0.74 cc. of pyridine, and 0.74 cc. of a 0.88-molar periodic acid solution is stirred in. mixture is kept for 1 /2 hours, diluted with water and saturated common salt solution and shaken three times with chloroform. The chloroformic solutions are'washed with 30 cc. of semi-saturated common salt solution, dried and evaporated in vacuo, and the residue is mixed with a solution of 400 mg. of potassium carbonate in 12 cc. of water and 24 cc. of alcohol. The solution is boiled for 1 hour in a current of nitrogen, allowed to cool, poured into semi-saturated common salt solution and shaken once With chloroform and three times With a 7:3 mixture of chloroform and alcohol. The organic extracts are washed with semi-saturated common salt solution, dried and evaporated in vacuo; the residue is dissolved in 3 cc. of pyridine and With ice cooling stirred into a solution of 100 mg. of chromium trioxide in 3 cc. of pyridine. The mixture is stirred for 3 hours at room temperature, dilute common salt solution and benzene are added, the mixture is vigorously shaken, filtered through Celite, the filter residue is washed with benzene, and the aqueous phase of the filtrate is again extracted with benzene. The organic solutions are then shaken twice with dilute common salt solution, the benzolic solutions are dried and evaporated, and the residue is chromatographed over 3 grams of alumina (activity H). The firstbenzene eluates contain the 18:11-lactone of d:l-A -3-ethylenedioxy-11 8- hydroxy-l6-oxo-androstene-18-acid which melts at 263- 268 C. after having been sublimed at 200 C. in a high vacuum and recrystallized from methylene chloride+ ether. It is identical with the compound described in Example 5.

Example 7 210 mg. of d:l-A -3-ethylenedioxy-11fi-acetoxy-16:18- dioxo-androstadiene are stirred into 20 cc. of methylethyl dioxolane distilled over lithium-aluminum hydride and 20 mg. of anhydrous ferric chloride. After stirring for 4 days all has passed into solution. The-mixture'is then poured-into dilute sodium bicarbonate solution and The twice extracted with benzene. The organic solutions are washed with saturated common salt solution, dried, and evaporated in vacuo, and the residue is chromatographed over 7 grams of alumina (activity 11). The benzene fractions contain d:l-A -3:18-diethy1enedioxy-1lit-acetoxy-l6-oxo-androstadiene. After having been recrystallized twice from acetone-I-ether with the addition of 1 drop of pyridine it melts at 250253.5 C.

Infrared spectrum in methylene chloride: 577,u+8.12,u (acetate); 5.84p.+5.90;.t+6.21,u (A -l6-ketone) and broad bands between 9.03, and 9.22a (ketals).

Example 8 A mixture of 30 cc. of freshly distilled ethylenedithiol and 15 cc. of absolute benzene is treated with a solution of 0.345 cc. of pyridine in 15 cc. of absolute methanol and 15 cc. of methanolic hydrochloric acid (prepared from 0.3 cc. of acetylchloride and 15 cc. of methanol). 3.08 grams of dzl A 3 ethylenedioxy 11 3 acetoxy 16:18 dioxo androstadiene are then stirred in. When all has passed into solution, the mixture is kept for 12 days at room temperature in a sealed vessel, then diluted with benzene, extracted twice with 150 cc. and seven times with 100 cc. of aqueous ammonia of 5% strength and then twice with water, and subsequently the aqueous solutions are shaken once with 200 cc. of ether. The organic solutions are dried and evaporated, and the residue is freed from high-boiling constituents at 60 C. in a high vacuum, then dissolved in cc. of benzene, and chromatographed over 90 grams of alumina (activity 11). Recrystallization of the benzene eluates from acetone-l-ether yields 1.86 grams of d:l-A -3- ethylenedioxy-l 6-ethylenedimercaptol l fi-acetoxy-l 8-oxoandrostadiene melting at 223-225.5 C. The infrared spectrum (solvent: methylene chloride) contains in the carbonyl area only one strong band at 5.76/p (aldehyde+ acetate) A mixture of 410 mg. of the llfl-acetoxy-thioketal described above, 35 cc. of methanol and 320 mg. of potassium carbonate in 10 cc. of water, sealed in an ampoule in vacuo, is immersed in a boiling methanol bath and stirred for 22 hours with a magnetic stirrer. After 12 hours all has passed into solution. The mixture is allowed to cool slowly to room temperature and then placed in a mixture of ice and common salt. Filtration, washing with ice-cold methanol of 70% strength, water, methanol of 70% strength and ether yields 300 mg. of the 18:11- cyclo-semiacetal of dzl A 3 ethylenedioxy 1119- hydroxy 16 ethylenedimercapto 18 oxo androstadiene melting at 220-221 C. The infrared spectrum displays a band at 2.79/ (hydroxyl) but no hands in the carbonyl area.

The cyclo-semiacetal-acetate prepared from 260 mg. of this cyclo-semiacetal, 4 cc. of pyridine and 4 cc. of acetanhydride melts at 198-200 C. after recrystallization from benzene-l-ether. Infrared spectrum in methylene chloride: 5.75p.+8.l5,u (acetate) 9.16; (ketal).

In the course of 1 /2 hours a solution of 2.2 grams of mercuric chloride in 9.5 cc. of acetone is stirred into a mixture of 1.25 grams of the above cyclo-semiacetalacetate, 30 cc. of acetone, 3 cc. of water and 1.95 grams of mercuric oxide. The whole is stirred for 18 hours at room temperature, filtered through Celite, the filter residue is washed with 750 cc. of acetone. The filtrate is concentrated to a small volume in vacuo at 30 C. bath temperature, then diluted with chloroform, extracted twice with potassium iodide solution of 40% strength and three times with water, and the aqueous solutions are then shaken with chloroform. The organic solutions are dried and evaporated and the residue is chromatographed over 50 grams of silica gel. The 3:1 benzene+ethyl acetate eluates contain d:l-A 3-ethylenedioxy-11,3:18- oxido-l6-oxo-l8-acetoxy-androstadiene. For purification it is dissolved in methanol, treated with 200 mg. of Carboraffin, filtered, the filter residue is washed with methanol, and the filtrate is concentrated and then allowed to crystallize. Yield: 400 mg. of the pure compound melting at 209-2105 C.

Example 9 10 grams of dzl-A -3-ethylenedioxy-11;3:18a-oxido- 16-oxo-l8a-methyl-l8-homo-androstatriene are dissolved with gentle heating in 150 cc. of benzene, then treated with 600 cc. of methanol and cooled to 0 C. 20 cc. of ice-cold 4 N-caustic soda solution are added to the resulting clear solution, the whole is thoroughly stirred, and 45 cc. of aqueous hydrogen peroxide of about 30% strength are added. The reaction mixture is left to itself for 24 hours at 0 to 5 C., with about 2.4 grams of natryl hydroxide (NaHO separating out in coarse crystals. While keeping the solution strongly stirred, 2.0 grams of 2% palladium-i-calcium carbonate catalyst are added in small portions and stirring is continued until no more oxygen escapes and no more hydrogen peroxide can be detected. When this point has been reached, the mixture is suction filtered, and the filter residue is washed with methylene chloride. 40 cc. of 2 N-acetic acid are added to the colorless filtrate and the whole is very extensively evaporated (160 to cc.) under reduced pressure. Crystallization of the epoxide sets in in the course of the evaporation. To complete the precipitation, 1 liter of water is added, and the mixture is kept overnight at 0 to 5 C. The crystals are then suctioned off, thoroughly washed with water and dried in vacuo over phosphorus pentoxide. Yield: 9.0 grams of d: 1-A -3-ethylenedioxy-1 15 18a; 14: 15-dioxido-16-oxo- 18a-methyl-l8-homo-androstadiene melting at 182-196 C. This product is sufliciently pure for treatment with osmium tetroxideperiodate. A specimen of the epoxide, recrystallized from methanol and benzene+hexane, melts at 199-201 C. Infrared spectrum in methylene chloride: bands at 5.72, (1600); 5.96;]. (enol ether) and 9.16 1 (ketal).

380 mg. of the above ketal epoxide in 6.4 cc. of glacial acetic acid and 5 cc. of water are immersed in a current of nitrogen for 15 minutes 'in a bath kept at 100 C.,

then evaporated in vacuo, benzene is added, the whole is again evaporated in vacuo, and the residue is repeatedly recrystallized from a mixture of benzene-i-ether+petroleum ether. The resulting d:l-A -3:l6-dioxo-l1fl:l8a; 14: l5-dioxido-l8a-methyl-l8-homo-androstadiene melts at 226-233 C. Characteristic bands of the infrared spectrum (solvent: methylene chloride): 5.72 t (S-ring- CO); 5.98;/. (3CO-l-dihydropyran) and 6.17; (A double bond).

A solution of 7.00 grams of dzl-A -3-ethylenedioxy- :18a; 14:15-dioxido 16 oxo 18a-methyl-l8-homoandrostadiene in 350 cc. of tetrahydrofuran is-first mixed with stirring with a solution of 7.88 grams of sodium periodate in 70 cc. of water, then with 7.88 grams of crystalline sodium acetate and finally with 70 mg. of osmium tetroxide. The tea-colored mixture which contains undissolved sodium acetate is stirred for 24 hours at room temperature, a white, flocculent precipitate separating out after a short time. After termination of the reaction time the reaction mixture is suction filtered, the filter residue thoroughly washed with methylene chloride, and as much as possible of the organic solvents is removed from the filtrate under reduced pressure at 35 C. bath temperature. The precipitate is suctioned ofl, thoroughly washed with water and dried in vacuo over phosphorus pentoxide to yield 7.27 grams of crude d :l-A -3 -ethylenedioxy-1 15: 18a; 14:15-dioxido-1 6-oxo-l 8: 1Sa-dihydroxy-l8a-methyl-18-homo-androstene melting at 174-178 C. If desired, the subsequent periodic acid cleavage can alternatively be performed with the washed, moist crude product. On recrystallization from methylene chloride+methanol a compound is obtained which 15 melts at 184-187 C. When the product is formed by oxidation with a molar proportion of osmium tetroxide a melting point of 200-202 C. may occasionally be observed. The infrared spectra of the two modifications are identical. Infrared spectrum in Nujol: bands at 2.89 (hydroxyl), 5.71, (l6-CO) and 9.15 (ketal).

The same compound can alternatively be obtained as follows:

4.82 grams of dzl-A l -3-ethylenedioxy-115:18; 14:15- dioxido 16 oxo-1Sa-methyl-l8-homo-androstadiene are dissolved in 100 cc. of tetrahydrofuran and cooled in ice, and in the course of minutes a solution of 3.18 grams of osmium tetroxide in 100 cc. of ether is stirred in dropwise, and the mixture is then kept for 24 hours at room temperature. 600 cc. of methanol and then a solution of 25 grams of ammonium sulfite in 600 cc. of water are then added, and the whole is stirred for 2% hours at room temperature. The mixture is suction filtered through a glass frit, the filter residue washed with 200 cc. of methanol, and the turbid filtrate concentrated to about 500 cc. with stirring under reduced pressure. The product is then repeatedly extracted with a 7:3 mixture of chloroform-i-alcohol. The extracts are washed with saturated common salt solution, combined, dried and evaporated to yield 4.01 grams of crude, crystalline dzl A 3-ethylenedioxy-11B:18a; 14:15-dioxido-16-oxo- 18: 18a dihydroxy-lSa-methyl-l8-homo-androstene. A specimen recrystallized from methylene chloride melts at 200-202 C.

7.27 grams of the crude 18:18a-diol described above are suspended in a mixture of 180 cc. of dioxane and 3 cc. of pyridine and treated with 30 cc. of a molar solution of periodic acid. The whole is then stirred for 8 hours at room temperature, treated With 350 cc. of methylene chloride and washed twice with 220 cc. of water on each occasion. The aqueous solutions are again shaken with 220 cc. of methylene chloride, and the methylene chloride solutions are combined dried and then evaporated in vacuo. Crystallization of the crude product from methylene chloride-l-ether yields 6.94 grams of dzl A 3-ethylenedioxy-11fi-acetoxy-14:15-oxido-16:18- dioxo-androstene melting at 188-189 C. The mother liquoryields another 0.36 gram of a slightly less pure product.

Example 10 A solution of 3.0 grams of d:l-A -3-ethy1enedioxy- 11B:18a;14:15 dioxido 16 oxo 18a-methyl 18- homo-androstadiene in 10 cc. of dry pyridine and 60 cc. of chloroform is treated at -17 for 26.5 minutes with turbination with an ozonized current of oxygen capable of yielding 16.3 mg. of ozone per minute. The reduction of the ozonide and processing are performed as described in Example 2 with 10 cc. of glacial acetic acid, 10 cc. of Water, 20 cc. of pyridine and about 10 grams of zinc dust. The crude product is chromatographed in benzene over 60 grams of alumina (activity II), the middle benzene eluates yielding 320 mg. of d:l-A -3-ethylencdioxy 11,8 acetoxy 14:15 oxido 16:18 'dioxo-androstene, melting at 176181 C., in crystalline form. After recrystallization from benzene-l-ether the melting point rises to 188-189 C. Infrared spectrum in methylene chloride: bands at 3.70;. (aldehyde); 5 .72,u. and 5.76 (16-CO, aldehyde-l-ester); 8.17u (acetate) and 9.13;r (ketal).

Example 11 A solution of 11.24 grams of d:l-A -3-ethylenedioxyllfl:18a;14:15 dioxido 16 oxo 18a methyl 18- of alumina (activity II).

of osmium tetroxide and 3.0 grams of sodium periodate are added. Finally, the mixture is stirred on for 9 hours and then poured into 500 cc. of water, extracted once with 500 cc. and twice with 350 cc. of methylene chloride on each occasion, and the extracts are Washed twice with 350 cc. of water on each occasion. The methylene chloride extracts are combined, dried and evaporated to yield 14.22 grams of a residue which crystallizes from ether; it is dissolved in a mixture of equal volumes of benzene and hexane and chromatographed over 225 grams 5.4 liters of a 1:1 mixture of benzene and hexane elutriate a total of 4.278 grams of starting material which melts at 201203 C. after recrystallization from methylene chloride-f-methanol. 900 cc. of benzene elutriate 876 mg. of a non-unitary product. The fractions elutriated with 1.8 liters of ethyl acetate are evaporated and the residue is triturated with ether, yielding 5.834 grams of a product melting at 173l81 C. According to its infrared spectrum and paper-chromatographic analysis it is almost pure dzl-A -3-ethylenedioxy-l lfi-acetoxy- 14: 15 -oxido- 1 6 18-dioxo-androstene.

Example 12 1.0 gram of dzl-A -3-ethylenedioxy-l1fi-acetoxy-14:15- oxido-16:18-dioxo-androstene is suspended in a mixture of 10 cc. of absolute methanol and 10 cc. of absolute tetrahydrofuran, cooled to 0 C., and 4.8 cc. of a 0.5 N- solution of soduim methylate in absolute methanol is added. The whole is then stirred until a clear solution is achieved (about 15 minutes) which is then kept for 50 to 60 hours at 0 to 5 C. with exclusion of moisture. 0.5 cc. of glacial acetic acid and 0.5 cc. of pyridine are then added, and the solution is concentrated at room temperature under reduced pressure to about 5 cc. The whole is then diluted with Water, extracted twice with methylene chloride, and the extracts are washed once 'with water. The combined methylene chloride extracts are evaporated to yield 1.08 grams of a crystalline residue which is recrystallized from methylene chloride-tether and yields a total of 638 mg. of the 18:11-cyclosem1'acetal of d:l-A -3-ethylenedioxy-1lfi-hydroxy-14z15-oxido- 16: 18-diox-o-androstene melting at 243248 C. A specimen recrystallized from methylene chloride+methanol melts at 251-254" C. Infrared spectrum in methylene chloride: bands at 2.79 (hydroxyl); 5.70 1. (16-CO) and 9.15;]. ('ketal).

The acetate is advantageously prepared from the crude hydrolysis product: 4.277 grams of the crude hydrolysis product are kept for 48 hours at room temperature in 30 cc. of pyridine and'20 cc. of acetanhydride, and during this time some of the acetate begins to crystallize out. The whole is then evaporated to dryness in a Water-jet vacuum, and the residue is repeatedly dissolved in benzene and again evaporated each time. The crude product is triturated with ether, the pure acetate (2.214 grams) remaining undissolved. Melting point 245253 C.'

The pure acetate crystallizes from methylene chloride+methanol in prismatic form; above 220 the prisms are turned into long needles which melt at 249-252 C. Infrared spectrum in methylene chloride: bands at 570 with a shoulder at 573 (ester-CO and 16-CO); 8113 1. (acetate) and 9.15 ('ketal).

While cooling with ice, 0.2 cc. of freshly distilled benzoyl chloride is stirred into a solution of 200 mg. of the 18 1 l-cyclo-semiacetal of d:1-A -3-ethylenedioxy-1 lfl-hydroxy-14:15-oxido-16:18-dioxoandrostene in 9 cc. of benzene and 1 cc. of pyridine. After 2 hours cooling with ice is discontinued, and the reaction mixture is left to itself overnight at room temperature, thenpoured into benzene and water and extracted twice with 0.1 N-sodium bicarbonate solution and three times with water. The aqueous solutions are then shaken twice with fresh benzene. The organic solutions are dried and evaporated, and the residue is repeatedly recrystallized from a mix- 17 ture of methylene chloride, acetone and ether. The resulting cyclo-semiacetal benzoate melts at 258.5264.5 C. and displays the following characteristic bands in the infrared spectrum: 5.69;; (-ring-CO); 5.78;; (benzoate) and 9.15;; (ketal).

Example 13 1.538 grams of d:1-A -3-ethylenedioxy-11B:18;14:15- dioxido-l6-oxo-l8-acetoxy-androstene are stirred in the presence of 1.0 gram of 10% palladium-l-calcium carbonate catalyst in 240 cc. of absolute ethanol under hydrogen. When the amount of hydrogen calculated for one molecular equivalent has been taken up (after 9 hours), the hydrogenation is discontinued, and the catalyst is filtered oif and washed with methylene chloride. Evaporation of the filtrate in vacuo yields 1.551 grams of a product which crystallizes readily from methylene chloride-l-ether. The crude product can be used directly for the elimination of water.

A specimen of d:l-A -3-ethylenedioxy-115:18-oxido- 14-hydroxy-16-oxo-lS-acetoxy-androstene, recrystallized twice from methylene chloride+ether, melts at 201.5- 203.5 C.

Infrared spectrum in methylene chloride: bands at 2.77;; and 2.87;; (free and combined hydroxyl); 5.73;; (ester-CO and 16-CO) and 8.13;; (acetate).

300 mg. of the cyclo-semiacetal-acetate described above are heated for 25 minutes at 100 C. in a mixture of 7.5 cc. of glacial acetic acid and 7.5 cc. of water. This solution is cooled, poured into 75 cc. of water and extracted three times with a 2:1 mixture of chloroform and alcohol, 100 cc. thereof being used on each occasion. The extracts are shaken with sodium bicarbonate solution and then with saturated common salt solution, dried and evaporated in vacuo, yielding a crystalline residue (300 mg.) from which by crystallization form methylene chloride-l-methanol a first fraction is obtained of 188 mg. of the cyclo-semiacetal of dzl-A -3zl6zl8-trioxo- 11B:14;8-dihydroxyandrostene melting at 239240 C. A further amount of a slightly less pure substance separates from the mother liquor. The compound retains the solvent very stubbornly. When dried at a high temperature, it turns brown with decomposition. Ultraviolet spectrum: maximum at 240 m;; (e=16,150). Infrared spectrum in Nujol: bands at 2.96;; (hydroxyl); 5.77;; (16-CO); 5.98;; and 6.18;; (azfi-unsaturated ketone).

2.51 grams of crude dzl-A -3-ethylenedioxy-l1p:18- oxido 14 hydroxy 16 oxo 18 acetoxy androstene are dissolved in 480 cc. of absolute benzene, 12.0 grams of neutra alumina (product of Messrs. Woelm; activity I) are added, and the mixture is refluxed for 2 hours while being stirred and with exclusion of moisture at 110 C. bath temperature, then cooled. The alumina, which by then has turned red, is suctioned 0E and thoroughly washed on the filter with methylene chloride. The filtrate is evaporated in vacuo, and the residue (2.22 grams, extinction at 232 m;;:14,300) is crystallized from ether to yield 1.63 grams of dzl-A -3-ethylenedioxy-l1ft:18-oxido-16-oxo-l8-acetoxy-androstadiene melting at 209-2105 C. Ultraviolet spectrum: 6 16,600. Infrared spectrum in methylene chloride: bands at 5.75;; (ester-CO); 5.84;; with shoulder at 5.90;; and 6.19;; (A -16-ketone); 8.18;; (acetate) and 9.08;;-9.16;; (ketal).

When the mother liquor is concentrated and allowed to stand for a prolonged period, a further quantity of a slightly less pure product crystallizes out.

Example 14 22.0 mg. of d:l-A -3-ethylenedioxy-11,6:18-oxido- 14-hydroxy-16-oxo-18-acetoxy-androstene and 11.2 mg. of benzoic acid in 2.0 cc. of absolute xylene are mixed with 0.08 cc. of a solution of triethylamine in xylene (containing 1.0 cc. of triethylamine in 10.0 cc. of solution) and refluxed for 12 hours under nitrogen at 160 C. bath temperature, then allowed to cool, diluted with benzene and washed with water, sodium bicarbonate solution and water, and the aqueous solutions are separately extracted twice with benzene. The benzene solutions are combined and dried and yield 28 mg. of crude product which displays an extinction of 11,600 at 231 m;;. Crystallization from ether yields 8.9 mg. of crystals melting at 207-209" C. which, after having been once more recrystallized from ether, melt at 217220.5 C. Analysis and infrared spectrum reveal that the product is dzl A 3 ethylenedioxy 115:18 oxido 14 hydroxy-16-oxo-18-benzoyloxy-androstene. Ultraviolet spectrum: e ,,=12,100. Infrared spectrum in methylene chloride: bands at 2.77;; and 2.86;; (free and combined hydroxyl); 5.72;; (16-CO); 5.79;; (benzoate) and 9.12;; (ketal).

From the mother liquor of the first crystallization a further 6.3 mg. of crystalline product are obtained; according to its mixed melting point and infrared spectrum it is identical with the d:lA -3-ethylenedioxy- 11,6:18 oxido 16 oxo 18 acetoxy androstadiene described above.

Example 15 500 mg. of pure dzl-A -3-ethylenedioxy-11p: 18-oxido- 16-oxo-1S-acetoxy-androstadiene are hydrogenated in 150 cc. of absolute ethanol with 500 mg. of 10% palladium calcium carbonate catalyst under atmospheric pressure at room temperature. The hydrogenation is discontinued when one molecular equivalent of hydrogen has been taken up (after about 7 hours). The catalyst is filtered off, the filtrate evaporated, and the residue is sprinkled with ether to cause complete crystallization. Melting point 212-22'6 C. After recrystallization from methylene chloride-i-ether the resulting d:l-A 3-ethy1,- enedioxy 115:18 oxido 16 oxo 18 acetoxyandrostene sublimes above 220 C. slowly to form small cubes melting at 243-246 C. Infrared spectrum in methylene chloride: bands at 5.74;; (16-CO and ester); 8.18;; (acetate) and 9.11;; (ketal).

A solution of 410 mg. of this acetate in 65 cc. of methanol is mixed with a solution of 540 mg. of potassium carbonate in 17.5 cc. of Water and kept for 20 hours at room temperature. 0.22 cc. of glacial acetic acid, 50 cc. of water and 200 cc. of saturated common salt solution are then added, and the mixture is extracted once with chloroform and three times with 70 cc. of a 7:3 mixture of chloroform and alcohol. The organic solutions are dried and evaporated, and the residue is recrystallized twice from methylene chloride-tether. The d: l-A -3-ethy1enedioxy-1 lp-hydroxy-lfi: 1 8-dioxo-androstene cyclo-semiacetal obtained in this manner melts at 253258 C. The infrared spectrum (solvent: methylene chloride) displays the following characteristic bands: 2.78;; (hydroxyl); 5.73;; (S-ring-CO) and 9.12;; (ketal).

250 mg. of the d:l-A 3-ethylenedioxy-1lB-hydroxy- 16:18-dioxo-androstene cyclo-semiacetal described above are dissolved with heating in 6 cc. of glacial acetic acid. 6 cc. of water are added, and the mixture is heated for 30 minutes at 100 C. in a current of nitrogen, then evaporated in vacuo and the last traces of glacial acetic acid and Water are removed by two additions of benzene and evaporation in vacuo. The residue, the cyclo-semiacetal of d:l-A -3:16:18-trioxo-11 fi-hydroxy-androstene, is repeatedly recrystallized from a mixture of methanol, methylene chloride and ether, and melts then at 242- 246 C. Characteristic bands of the infrared spectrum in Nujol: 2.85;; (hydroxyl); 5.73;; (S-ring-CO) and 6.05;;+6.20;; (A -3-ketone). e ,,=16,500.

mg. of the cyclo-semiacetal of dzl-A -3-ethylenedioxy-11fi-hydroxy-16:18-dioxo-androstene are stirred with ice cooling into a mixture of mg. of chromium trioxide and 3 cc. of pyridine. After 15 minutes the ice cooling is discontinued, the mixture is stirred for another 4 hours at room temperature, and benzene and semisaturated common salt solution are added. The whole is 19 filtered through Celite, the filter residue washed with benzene, the aqueous phase of the filtrate is extracted twice with benzene, and the benzolic solutions are shaken three times with semi-saturated common salt solution. The organic solutions are dried and evaporated, and the residue is recrystallized repeatedly from acetone-l-ether and pure acetone. It melts at 259266 C. and is identical with the 18:11-lactone of dzl-n -3-ethylenedioxy-l6- 'oxo-l1 8hydroxy-androstene-18-acid described in Example 5.

Example 16 150 mg. of the free cycle-semiacetal of d:l-,A -3-ethyl ene-dioxy 11,8 hydroxy 14: 15 oxide-16: 18-dioxo-androstene are hydrogenatedas described for the acetate in Example 13with 100 mg. of palladium-l-calcium carbonate catalyst in 25 cc. of absolute ethanol. Crystallization of the crude product from a mixture of methylene chloride, methanol and ether yields 124 mg. of d:l-A -3-ethylenedioxy-115:14-dihydroxy-16: 18-diox0- androstene cyclo-semiacetal melting at 247249 C. (with decomposition). Infrared spectrum in Nujol: bands at 288 and 2.94 4 (hydroxyl); 5.74 (16-CO) and 9.16 (ketal).

50 mg. of this cyclo-semiacetal are acetylated overnight in 2 cc. of pyridineand 1 cc. of acetanhydride, then diluted with 10 cc. of absolute benzene, 2.0 cc. of methanol are added, and after 2 hours the reaction mixture is worked up in the usual manner. Crystallization of the crude product (67 mg.) from methylene chloride-f-ether yields 40 mg. of d:1-A -3-ethylenedioxy-11,8:18-oxido-14- hydroxy-l6-oxo-18-acetoxy-androstene; according to its melting point, mixed melting point and infrared spectrum it is identical with the compound described in Example 13.

Example 17 2 cc. of acetyl chloride are stirred into a mixture of 200 cc. of dry benzene, 2.3 cc. of absolute pyridine and 2 cc. of absolute methanol. After 20 minutes 16 grams of dzl-A -3-ethylene-dioxy llfl-hydroxy 14:15 oxido- 16:18-dioxo-androstene cycle-semiacetal and 250 cc. of

' dihydropyran are added. The whole is stirred for 96 hours at room temperature with exclusion of moisture, then diluted with benzene and extracted with dilute sodium bicarbonate solution and three times with water. The aqueous solutions are shaken twice with benzene, and the organic solutions are then combined, dried, and evaporated in vacuo .at 50 C. Readily volatile constituents are removed at 50 C. in a high vacuum, and the residue is dissolved in benzene and filtered through 80 grams of alumina (activity II). The first 2 liters of the filtrate contain (1: 1-A -3-ethylenedioxy-11B:18;14: -dioxido-16- oxo-l8-tetrahydropyranyloxy-androstene in the form of a mixture of the stereoisomers. A first crystallization from methylene chloride-l-ether yields 15.24 grams of a product melting at 193201 C. (with decomposition). The infrared spectrum in methylene chloride no longer contains a hydroxyl band. In the carbonyl area only the 5- ring-ketone band is observed at 5.7 10.21 grams of the dzl-A -3-ethylenedioxy-l1/3:18;14:15-di-oxido-16-oxo 18- tetrahydropyranyloxy-androstene described above in 800 cc. of absolute ethanol are mixed with 5.0 grams of 10% palladium-l-calciurn carbonate catalyst and shaken until 1 molecular equivalent of hydrogen has been taken up. The catalyst is then filtered off, Washed on the filter with methylene chloride, and the filtrate is evaporated to dryness in a water-jet vacuum. The resulting crude d:l-A5-3-ethylenedioxy-11B:18 oxido 14 hydroxy-16- oxo-lS-tetrahydropyranyloxy-androstene can be used as it is for the elimination of water described below. A specimen of the pure 14-hydroxy compound, recrystallized from methylene chloride-hether melts at 184186 C. Infrared spectrum in methylene chloride: 2.78 2.85 1 (hydroxyl) and 5.73 (5-ring ketone).

10.30 grams of the above crude 14-hydroxy compound are dissolved in 1 liter of absolute benzene and refluxed for 3 hours while being stirred with 30 grams of neutral alumina (activity I) in a current of nitrogen. After cooling, the alumina is suctioned ofi, washed on the filter With 300 cc. of benzene, and the pale-yellow filtrate is evaporated to dryness in a water-jet vacuum. Crystallization of the residue (9.4 grams) from ether yields in two fractions a total of 8.23 grams of pure (id-A 6- ethylenedioxy 11,6:18-oxido-16-oxo 18 tetrahydropyranyloxy-androstadiene. After having been again recrystallized from ether, the compound melts at 161163 C. Ultraviolet spectrum: maximum at 236 m (=16,300). Infrared spectrum in methylene chloride: 5.85,u+6.20 .L (A -16-ketone) mg. of the 18:11-semiacetal of d:l-A -3-ethylenedioxy-11fi-hydroxy-14:15-oxido 16: 18 dioxo androstene, used as starting material in the foregoing example, are suspended in 20 cc. of glacial acetic acid and immersed in an oil bath kept at 100 C. After 2 minutes 1.0 cc. of water is added to the clear solution. After another 5 minutes at 100 C. the whole is poured into 30 cc. of water, repeatedly extracted with methylene chloride, and the extracts are Washed With dilute sodium 'bicarbonate solution until neutral. The methylene chloride solutions are combined and dried and yield 84 of a crystalline residue. Recrystallization from methylene chloride-l-ether yields the pure 18:1l-sezniacetal of d:l-A -3:16:18-trioxo-11,8-hydroxy-14:15-oxido androstene melting at 244-2465 C. (with decomposition). Ultraviolet spectrum: maximum at 238 m (e=15,200). Infrared spectrum in Nujol: 2.98 (hydroxyl); 5.73 (5- ring-ketone) and 5.9,5u+6.18 A -3-ketone).

Proceeding in exactly identical manner, reaction of the 18-tetrahydropyranyl ether with the 18-acetate of the semiacetal described in Example 16 yields the same semiacetal of d:l-A -3:l6:18-trioxo-11B-hydroxy-14:15-0xidoandrostene melting at 244-2465 C.

Example 18 100 mg. of d:l-A -3-ethylenedioxy 16 oxo-11f3:18- oxido-1S-tetrahydropyranyloxy-androstadiene are stirred with 25 cc. of absolute ethanol and 10 mg. of a 10% palladium+calcium carbonate catalyst in a current of hydrogen until the quantity of hydrogen required to saturate the 14:15-double bond has been taken up. The catalyst isthen filtered off, washed on the filter with benzene, and the filtrate is evaporatedto dryness in vacuo. After recrystallization from methylene chloride-l-ether the re sulting d:l-A -3-ethylenedioxy-16-oxo 115218 oxido-18- tetrahydro-pyranyloxy-androstene melts at 213219 C. Infrared spectrum in methylene chloride: 5.74 1. (S-ringketone) and 9.12 (ketal). V

75 mg. of the hydrogenation product obtained as described above are heated for 30 minutes at 100 C. in a current of nitrogen with 10 cc. of glacial acetic acid of 50% strength. The mixture is then evaporated in vacuo, the residue is taken up in benzene, once more evaporated, and the whole operation is repeated once more. Recrystallization of the residue from methanol+ether yields the cyclo-semiacetal of d:l-A -3:16:18-tn'0xo 11/3 hydroxyandrostene which gives no melting point depression with the product described in Example 15 and has an identical infrared spectrum.

What is claimed is V 1. Process for the manufacture of 11:18-dioxygenated 16-oxoandrostane compounds, wherein in a member selected from the group consisting of a A -3:16-dioxo 11,6:18a-oxido-18a-methyl-l8-homorandrostadiene and a 3-ketal thereof, the 18 :18a-double bond is subjected to oxidativecleavageby ozonization and reductive splitting of the ozonides, and the llfl-acetoxy group in the resulting '11,8-acetoxy-18-oxo compound is hydrolyzed in an alkaline medium- .2- A Pro e f l m e e n he andr s adicn '21 starting material contains a carbon to carbon double bond in the 14:15 position.

3. A process of claim 2, wherein the carbon to carbon double bond is temporarily protected during the reaction.

4. A process of claim 2, wherein the 16-ox0 group is temporarily protected during the reaction.

5. Process wherein hydrogen peroxide is caused to react with the A -3-ethylenedioxy-11,8:18a-oxido-16- x0-1Sa-methyl-l8-homo-androstatriene in alkaline solution, the 18:18a-double bond in the resulting 14:15- epoxide is subjected to oxidative cleavage by ozonization and reductive splitting of the ozonides, the resulting 11,8-acetoxy group is hydrolyzed with sodium methoxide, the resulting cyclosemiacetal is treated with a member selected from the group consisting of esterifying and etherifying agents, the product obtained is hydrogenated in the presence of a palladium catalyst and water is split off from the resulting 14-hydroxy compound.

6. Process wherein hydrogen peroxide is caused to react with the A -3-ethylenedioxy-11,8:l8a-oXido-16- oXo-18a-methyl-18-homo-androstatriene in alkaline solution, the l8zl8a-double bond in the resulting 14:15- epoxide is subjected to oxidative cleavage by hydroxylation of the enol double bond with a member selected from the group consisting of osmium tetroxide, potassium permanganate and an alkali metal perhalate and splitting up the diol formed with a member selected from the group consisting of periodic acid, lead tetraacetate and sodium bismuthate, the resulting llp-acetoxy group is hydrolyzed with sodium methoxide, the resulting cyclosemiacetal is treated with a member selected from the group consisting of esterifying and etherifying agents, the product obtained is hydrogenated in the presence of a palladium catalyst and water is split off from the resulting 14-hydroxy compound.

7. Process according to claim 6, wherein the 18:18adouble bond is split up with sodium periodate in the presence of pyridine and a catalytic quantity of-osmium tetroXide.

8. Process according to claim 6, wherein the 18:18adouble bond is first hydroxylated and the resulting 18:18a-diol split up with periodic acid.

9. Process according to claim 8, wherein the 18:18adouble bond is hydroxylated with sodium periodate in the presence of sodium acetate and a catalytic quantity of osmium tetroxide.

10. A -3-ethylenedioxy 115 acetoxy 16:18 dioxo androstadiene.

1 l. A -3-ethylenedioxy-1 1B-acetoXy-14: 15-oxido-16: 18- dioXo-androstene.

12. A compound selected from the group consisting of A -3:16:l8-trioXo-1lfi-hydroxy-androstene and its 18 1 l-cyclohemiacetal.

-13. Compounds selected from the group consisting of those of the formula wherein R represents a member selected from the group consisting of a free hydroxyl group, an esterified hydroxyl group derived from an acid selected from the group consisting of a lower aliphatic carboxylic acid, a lower monocyclic araliphatic acid and a monocyclic carbocyclic carboxylic acid, and an etherified hydroxyl group derived from an alcohol selected from the group consisting of a lower alkanol, monocyclic aralkanol and a-pyranol, and 3-ketals thereof.

22 14. A 3 ethylenedioxy 11,6:18;14:15-bis-oxido-16- oxo-l8-tetrahydropyranyloxy-androstene.

15. Compounds selected from the group consisting of those of the formula wherein R is a member selected from the group consisting of a free hydroxyl group, an esterified hydroxyl group derived from an acid selected from the group consisting of a lower aliphatic carboxylic acid, a lower monocyclic araliphatic acid and a monocyclic carbocyclic carboxylic acid, and an etherified hydroxyl group derived from an alcohol selected from the group consisting of a lower alkanol, monocyclic aralkanol and u-pyranol, and 3-ketals thereof.

16. A 3 ethylenedioxy-llfi: l8-oxido14-hydroxy-l6- 0140- 1 8 -tetrahydropyranyloxy-androstene.

17. Compounds selected from the group consisting of those of the formula wherein R is a member of the group consisting of a free hydroxyl group, an esterified hydroxyl group derived from an acid selected from the group consisting of a lower aliphatic carboxylic acid, a lower monocyclic araliphatic acid and a monocyclic carbocyclic carboxylic acid, and an etherified hydroxyl group derived from an alcohol selected from the group consisting of a lower alkanol. monocyclic aralkanol and ot-pyranol, and 3-ketals thereof.

18. A -3-ethylenedioxy-l 1B: 18-oXido-l6-oXo-18-tetrahydropyranyloxy-androstadiene.

19 A 3 ethylenedioxy 11,8:18 oxido-l6-oxo-18- acetoXy-androstadiene.

20. Compounds selected from the group consisting of those of the formula oxy-androstene.

23 23. The 18:11-lactone of A -3-ethylenedioxy-1lfi-hydroXy-16-oXo-androstadiene-18-acid.

24. The 18: ll-lactone of A -3-ethylenedioxy-l1 8hy droxy-l6-0Xo-androstene-18-acid.

25. A 16-oxo-androstene compound selected from the group consisting of those of the formula having a double bond extending from the S-carbon atom, wherein R stands for a member selected from the group consisting of a free and a ketalized 0x0 group, R stands for a member selected from the group consisting of a free hydroxyl group, an esterified hydroxyl group, a hydroxy group acetalized With an aldehyde group in the 13-position, a hydroXy group lactonized with a carboXyl group in the 13-position and an oxo group, R stands for a member selected from the group consisting of an aldehyde group, an aldehyde group semiacetalized with an ll-hydroxyl group, an ester and an ether of such cyclosemiacetal group, the ester being derived from an acid selected from the group consisting of a lower aliphatic carboxylic acid, a lower monocyclic araliphatic acid and a monocyclic carbocyclic acid and the ethers being derived from an alcohol selected from the group consisting of a lower alkanol, monocyclic aralkanol and u-pyranol; a carboXyl group, a carboxyl group lactonized with an ll-hydroxyl group, and their derivatives having a double bond also in the 14: l5-position.

26. Process for the manufacture of 11:18-dioXygenated 16-oxo-androstane compounds, wherein in a member selected from the group consisting of a A -3zl6-dioxo- 11,8:18a-oxidol8a-methyl-18-homo-androstadiene and a 3-ketal thereof, the 18:18ct-double bond is subjected to oxidative cleavage by treatment with hexavalent chromium, and the 11,8-acetoxy group in the resulting 115- acetoxy-18-oxo compound is hydrolyzed in an alkaline medium.

27. A process of claim 26, wherein the androstadiene starting material contains a carbon to carbon double bond in the 14:15 position.

28. A process of claim 27, wherein the carbon to carbon double bond is. temporarily protected during the reaction.

29. A process of claim 27, wherein the 16-oXo group is temporarily protected during the reaction.

30. Process for the manufacture of 11:18-dioxygenated 16-oXo-androstane compounds, wherein in a member selected from the group consisting of a A -3zl6-dioxo- 1 1B: 18a-oxido-1Su-methyL18-homo-androstadiene and a S-ketal thereof, the l8zl8a-double bond is subjected to oxidative cleavage by hydroxylation of the enol double bond with a member selected from the group consisting of osmium tetroXide, potassium permanganate and an alkali metal perhalate and splitting up the diol formed with a member selected from the group consisting of periodic acid, lead tetraacetate and sodium bismuthate, and the llfi-acetoxy group in the resulting llfi-acetoxy- 18-oXo compound is hydrolyzed in an alkaline medium.

'31. A process of claim 30, wherein the androstadiene starting material contains a carbon to carbon double bond in the 14:15 position.

32. A process of claim 31, wherein the carbon to carbon double bond is temporarily protected during the reaction.

33. A process of claim 31, wherein the 16-oxo group is temporarily protected during the reaction.

34. Process wherein hydrogen peroxide is caused to react with the A -3-ethylenedioxy-11,8:l8ot-oXido-16- oxo-lSa-methyl-l8-homo-androstatriene in alkaline solution, the 18:18a-double bond in the resulting 14:15- epoXide is subjected to oxidative cleavage by treatment with hexavalent chromium, the resulting llfi-acetoxy group is hydrolyzed with sodium methoxide, the resulting cycloserniacetal is treated with a member selected from the group consisting of esterifying and ethen'fying agents, the product obtained is hydrogenated in the presence of a palladium catalyst and water is split oil? from the resulting 14-hydroxy compound.

References Cited in the file of this patent UNITED STATES PATENTS Wettstein et al. July 1, 1958 Wettstein et al. July 22, 1958 OTHER REFERENCES UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2,994,694 August 1, 1961 Albert Wettstein et al0 It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, formula VII should appear as shown 'below instead of as in the patent:

column 7, line 55," after "acetic" insert acid column 8', line 27, for "its" read the column 9, line 17, for "=50 C, read 5 C, line 27, after "33" insert grams line 34, for "ggfflhmpi" read mp same column 9, line 69, for "-A =14-3-" read -A -3- column 10, line 6, for "233 m/u" read 233 mu column 12, line 11, for "(1.VJ" read (i av.) line 12, for "5,65/ read 5,65p, line 13, for "5.7l/ (l6-CO) 9. l/u" read 5, 71, (16430) 9 14 column 13, line 9, for "g read g' llne 38, for "5,76/ read 5.76 same column 13, line 53, for "2.79/u" read 2.79p, column 16, line 62, for "8:13p," read @25 Signed and sealed this 24th day of April 1962,. Attest:

ESTON G. JOHN-SON DAVID L. LADD Attesting Officer Commissioner of Patents 

1. PROCESS FOR THE MANUFACTURE OF 11:18-DIOXYGENATED 16-OXOANDROSTANE COMPOUNDS, WHEREIN IN A MEMBER SELECTED FROM THE GROUP CONSISTING OF A $4:18-3:16-DIOXO11B:18A-OXIDO-18A-METHYL-18-HOMO-ANDROSTADIENE AND A 3-KETAL THEREOF, THE 18:18A-DOUBLE BOND IS SUBJECTED TO OXIDATIVE CLEVAGE BY OZONIZATION AND REDUCTIVE SPLITTING OF THE OZONIDES, AND THE 11B-ACETOXY GROUP IN THE RESULTING 11B-ACETOXY-18-OXO COMPOUND IS HYDROLYZED IN AN ALKALINE MEDIUM. 